Vasopressin and oxytocin have crucial roles in the maintenance of plasma volume and osmolality and in various reproductive functions in mammals. These hormones are secreted by the magnocellular neuroendocrine cells of the hypothalamo-neurohypophysial system. There is clear evidence that endogenous opioids inhibit the electrical and secretory activity by direct actions on these neurons but the mechanisms of action and selectivity for oxytocinergic or vasopressinergic neurons are not clear. The opioid effects show tolerance and dependence, and are physiologically relevant since application of the opioid antagonist naloxone may also affect hormone secretion indicating a tonic opioid input. The effects of exogenous opioids on these neuroendocrine cells show tolerance and dependence, a clear indication that the normal function of these neurons is impaired in humans chronically using opioids in drug abuse or therapeutic situations. The goal of the research proposed here is to investigate the effects of opioids on specific ionic conductances in the membrane of the cell body and the axon terminals of oxytocinergic and vasopressinergic neurons. To achieve these objectives, whole-cell voltage clamp techniques will be used to investigate the nature of opioid receptors on the neurons, the effect of receptor activation on various voltage-gated and voltage-insensitive ionic currents, and the nature of receptor-ion channel coupling. Recordings made under current clamp will permit the overall effects of opioids on membrane potential and firing activity to be examined. Recordings will be made from dissociated neuroendocrine cells of the adult supraoptic nucleus and from isolated axon terminals dissociated from the neurohypophysis. This approach permits effects on excitability at the level of the cell body and effects on excitation-secretion coupling to be studied at the level of the axon terminal. These studies will provide important novel information on opioid mechanisms within this neuroendocrine system which is considered as a model for all mammalian neuroendocrine cells. Further, the studies will be unique in that neurotransmitter effects will be studied electrophysiologically within a single neuronal system at the level of the cell body and the axon terminal.